Population-Scale Pharmacogenomics to Improve Testing in Diverse Populations
Abstract (summary)
Pharmacogenomics (PGx) is the application of genetics towards precision medicine in drug selection and dosing. PGx studies have been hampered by lack of inclusion of diverse populations which has limited application for many groups and has resulted in clinical guidelines which include race-based decisions. In addition, genotyping coverage within PGx testing has been limited which has hampered discovery. Biobank cohorts offer the opportunity to utilize diverse populations which link electronic health record (EHR) data to genetics. This dissertation aimed to characterize the genetic diversity within PGx using large biobank cohorts with whole genome sequencing (WGS) data.
Characterization of genetic variation in 15 PGx genes (excludes CYP2B6) was completed using the All of Us Research Program. Significant deviations in allele and phenotype frequencies from known values were found. The analysis further reported that 20% participants have been exposed to a medication which would be impacted by their genetically predicted phenotype. Lastly, over 17,000 novel exome variants were identified within the PGx genes.
We further developed novel approaches for haplotyping of genes with complex genetic variation efficiently at scale. This method allowed for characterization of the diversity within CYP2D6 and aided in identifying limitations of current genotyping technology in predicting phenotype in select genetic ancestry groups. These differences were clinically significant as novel associations were discovered using WGS derived CYP2D6 phenotype compared to targeted genotyping methods.
Additional development included a novel approach to estimate drug dosing from EHR and medication exposure data using warfarin as the prototype drug. This method allowed for the discovery of 99 novel variants associated with warfarin dosing which replicated in two biobank cohorts. Importantly, 4 of the variants were found to have linkage disequilibrium with the CYP2C Cluster variant previously found to only be associated in African participants.
Collectively, this work reduces the knowledge gap in underrepresented groups towards equitable application of precision medicine. This work serves as a foundation to influence change in the field in terms of selection of variants to be included in testing, importance of increased diversity in genomics, and the necessity to revisit existing clinical guidelines to remove race-based medicine decisions.
Indexing (details)
Health sciences;
Genetics
0566: Health sciences
0369: Genetics
